A potentially important difference between leuprolide and degarelix lies in the significant reduction of pituitary, FOLLICLE STIMULATING HORMONE, FSH secretion by degarelix, an action not shared by Lupron. While both drugs suppress serum testosterone by inhibiting the secretion of luteinizing hormone (LH), sustained suppression of FSH secretion is unique to GnRH antagonists such as degarelix. This has been hypothesized to be the basis of the superior inhibition of prostate cancer growth and the lesser cardiotoxicity of the drug.

Suppression of Pituitary FSH secretion:  Degarelix rapidly reduces serum FSH by 80% by day 1, 75% on day 15, and results in a sustained reduction of 89% below baseline over the ensuing year.  In contrast, leuprolide lowers the initial serum FSH levels by 76% by day 14, but then the level rises to stabilize at 55% of baseline thereafter. Other studies of leuprolide report a 66% reduction of FSH by 10 – 11 weeks followed by a sustained rise to 10 – 20% below baseline between weeks 25 and 97.

A comparison of FSH levels between degarelix and leuprolide was presented in poster form at the 2016 Society of International Urologists, October 2016 by Crawford et al., based on 1 year comparison data from the study by Klotz, BJU Int, 2008. Their findings:

  1. Both FSH and LH levels increase with age.
  2. At 3 months degarelix reduced FSH levels ~97%  from baseline and this reduction was sustained for 13 months. Leuprolide reduced FSH by ~55-60% at 3 months.
  3. “Greater FSH suppression is related to greater PSA suppression only for patients treated with [degarelix].”
  4. “… FSH suppression to very low levels may have a direct anti-tumor effect.”

Although not fully explained, but possibly due to loss of negative feedback on pituitary FSH secretion, orchiectomy dramatically increases FSH levels.

Tissue Location of FSH Receptors:

FSH receptors are present at low levels in normal and malignant prostate cells, in the inner lining of tumor blood vessels, on the surface of T lymphocytes, and in lymph nodes, testes, and at other locations. Prostate cells themselves secrete FSH.  FSH receptors are found in benign and malignant prostate cells and their abundance increases as the disease becomes more aggressive, increasing even more in metastases. Activation of these receptors and their downstream signaling leads to a variety of biologic consequences to be discussed below. Suppression of pituitary FSH secretion by degarelix results in reduction in these biologic responses.

What is the Biologic Function of FSH? How Might It Be Important in the Treatment of Prostate Cancer?

As with any cellular receptor when joined by its matching signal (termed a “ligand”), when FSH activates its specific receptor a cascade of molecular signaling follows. The biologic result of FSH receptor stimulation is 1), increased cellular proliferation (i.e. cancer growth), and 2), the promotion of new blood vessel formation (termed “angiogenesis”) at the advancing edge of the prostate tumor mass.


Extensive research on this issue was reported in the New England Journal of Medicine, 2010, by Radu et al., “Expression of Follicle-Stimulating Hormone Receptor in Tumor Blood Vessels.”  Although the best recognized action of FSH is the conversion of female testosterone into estrogen, of special interest to this article is the expression of FSH receptors in the inner lining of blood vessels at the periphery (the outer 10 mm) of the growing prostate tumor mass. This results in a proliferation of new blood vessels at the invasive front of the tumor. The abundance of these new blood vessels at the growing edge of the tumor offers a greater opportunity for malignant cells to enter the blood stream. The proposed mechanism underlying this angiogenesis is the up-regulation of vascular endothelial growth factor (VEGF). The research by Radu was based on prostate cancer tissue from 773 patients and confirmed this location of receptors in the blood vessel lining surrounding malignant, but not in normal, prostate tissue.

The authors’ conclusion: Stimulation of endothelial FSH receptors promotes angiogenesis which “may substantially enhance the proliferation and migration of endothelial cells in cancer,” promoting cancer growth and increasing the opportunity for migration of cancer cells into the blood stream.

FSH as a mitogen, i.e a promoter of cellular proliferation and cancer growth:

Work by Mariani et al. (J Urol. June 2006) established that minimal FSH receptor expression was seen in normal  or BPH prostate cells, but was increased in malignant cells. A study by Ben-Josef et al. (J Urol. 1999) found that the expression of FSH receptors was up-regulated in hormone-refractory prostate cancer. And Siraj et al. ( BioMed Central. 2013) reported that the microvasculature of metastases expressed more FSH receptors than the cancer deeper within the prostate. The conclusion of these studies and others indicates that there is an abundance of tissues displaying FSH receptors which are targets for activation by serum FSH secreted from the pituitary gland and prostate cancer cells.

What are the consequences of FSH receptor activation?

This question leads to pointing out an excellent review article by David Crawford, MD, Chairman of the Department of Surgery at the University of Colorado, in association with other prominent urologists and experts in prostate endocrinology: “The Role of the FSH System in the Development and Progression of Prostate Cancer,” American Journal of Hematology/Oncology, June 2016.

In addition to discussing the points mentioned above in detail, the article additionally indicates:

  1. An important negative regulator of FSH secretion, prostatic inhibin peptide (PIP), arises from the prostate itself and functions as a check on pituitary FSH secretion. PIP expression progressively decreases as the grade of prostate cancer increases thereby reducing its suppressive effect on FSH secretion.
  2. The article reported many of the studies showing the sustained reduction of pituitary FSH resulting from degarelix and the substantially incomplete reduction seen with leuprolide.
  3. Citing his own study comparing degarelix vs leuprolide, Crawford et al, J Urol. 2011, stated that “patients on degarelix had a lower risk (34%) of PSA failure compared with leuprolide, and the risk of PSA failure decreased in patients who switched from leuprolide to degarelix.” Interestingly, degarelix more effectively suppressed FSH by almost 35% compared to leuprolide.
  4. “A recent analysis of 6 phase 3 prospective randomized trials reported that the risk of developing adverse cardiac events was significantly lower [by 50%] in patients receiving degarelix when compared to those receiving leuprolide,” (Albertson, Klotz, Tombal, Eur Urol 2014). Cardiac events in this study included: arterial embolic or thrombotic events, hemorrhagic or ischemic cardiovascular conditions, myocardial infarction, and other ischemic heart conditions occurring within one year of initiating therapy. [Reviewed in PCa COMMENTARY June 2016/

The authors’ conclusion in the Crawford article: “Since one of the main differences between chronic agonist [leuprolide] and chronic antagonist [degarelix] treatment is their effect on FSH, it is plausible that the long-term benefits from antagonists may be due, at least in part, to their profound suppression of the FSH system.”

BOTTOM LINE:  The significant reduction in FSH levels by degarelix is well established. A beneficial effect of this FSH reduction on cancer growth and decreased cardiotoxicity is strongly suggested by data, but will be further clarified by additional studies.